Sulfonamides

ABSTRACT

Compounds of the formula: ##STR1## where A, B, R 1  -R 8  are as described herein are endothelin inhibitors that can be used in treating diseases associated with endothelin, such as high blood pressure. Chemical synthesis of these compounds and pharmaceutical compositions containing these compounds are also useful.

This patent application is filed pursuant to 35 U.S.C. §371 based onPCT/EP95/04843, filed Dec. 8, 1995.

The present invention is concerned with novel sulphonamides and theiruse as medicaments. In particular, the invention is concerned with novelcompounds of the formula ##STR2## wherein R¹ signifies phenyl or phenylsubstituted by halogen, C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇ -alkylenedioxy,carboxyl or trifluoromethyl; or heterocyclyl selected from mono- orbicyclic, 5- and 6-membered heterocycles having oxygen, nitrogen orsulphur as the hetero atom;

R² signifies tetrazolyl, C₁₋₇ -alkyl-substituted tetrazolyl, cyano,carboxy, C₁₋₇ -alkoxycarbonyl, hydroxymethyl, formyl, carbamoyl,thiocarbamoyl, amidino or hydroxyamidino;

R³ signifies a residue --O--(CR^(a) R^(b))_(n) --OR⁹ ;

R⁴ -R⁸ signify hydrogen, C₁₋₇ -alkoxy or halogen;

R⁹ signifies hydrogen, benzyl, benzyl substituted in the phenyl ring byhalogen, C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇ -alkylenedioxy, carboxyl ortrifluoromethyl; or a residue --C(O)NHR¹⁰ ;

R¹⁰ signifies C₁₋₇ -alkyl, phenyl, phenyl substituted by halogen, C₁₋₇-alkyl, C₁₋₇ -alkoxy, C₁₋₇ -alkylenedioxy, carboxyl or trifluoromethyl;or pyridyl or pyridyl substituted by 1 or 2 C₁₋₇ -alkyl groups;

R^(a) and R^(b) signify hydrogen or C₁₋₇ -alkyl;

n signifies 2, 3 or 4; and

A and B signify CH; or one of the symbols A or B signifies nitrogen andthe other signifies CH; or

R² signifies hydrogen and one of the symbols A or B signifies N-oxide(N→O) and the other signifies CH,

and pharmaceutically usable salts of compounds of formula I.

Examples of residues of mono- or bicyclic, 5- and 6-memberedheterocycles having oxygen, nitrogen or sulphur as the hetero atom, suchas 2- and 3-furyl, 2-, 4- and 5-pyrimidinyl, 2-, 3- and 4-pyridyl, 1,2-and 1,4-diazinyl, 2- and 3-thienyl, oxazolyl, thiazolyl, imidazolyl,benzofuranyl, benzothienyl, purinyl, quinolyl, isoquinolyl andquinazolyl, which residues can be substituted, e.g. by 1 or 2 C₁₋₇-alkyl groups. Preferred are pyridyl or pyridyl substituted by 1 or 2C₁₋₇ -alkyl groups.

The term "C₁₋₇ " used here denotes groups with 1-7 C atoms, preferably1-4 C atoms. Alkyl and alkoxy groups can be straight-chain or branched.Methyl, ethyl, propyl, isopropyl, butyl, sec. and tert.butyl areexamples of such alkyl groups. Halogen denotes fluorine, chlorine,bromine and iodine, with chlorine being preferred.

A preferred group of compounds of formula I comprises those in which Aand B are CH or one of the symbols A and B is nitrogen. R¹ is preferablya phenyl residue, which is mono- or di-substituted, or a pyridylresidue, which is mono-substituted by C₁₋₇ -alkyl, especially an C₁₋₇-alkyl substituted 2-pyridyl residue. R² is preferably a tetrazolylresidue. R³ is preferably --O(CH₂)_(n) OH, --O(CH₂)_(n) O-benzyl or--O(CH₂)_(n) OC(O)NHR¹⁰, in which R¹⁰ is pyridyl, especially 2-pyridyl.n is preferably 2. Of particular interest among these compounds arethose in which R⁴ is C₁₋₇ -alkoxy and R⁵ -R⁸ are hydrogen; or R⁴ ishalogen, R⁷ is C₁₋₇ -alkoxy and R⁵, R⁶ and R⁸ are hydrogen; A isnitrogen and B is CH.

The documents, EP-A-0 510 526 and EP-A-0 526 708 disclose sulfonamideshaving endothelin-inhibiting activity.

The compounds of formula I can be manufactured by

a) reacting a compound of formula II ##STR3##

wherein R¹² is 3- or 4-cyanophenyl or 2- or 4-pyridyl N-oxide and Hal ishalogen and the remaining symbols have the significance set forth above,

with a compound of the formula MO--(CR^(a) R^(b))_(n) --OR⁹¹, wherein Mis an alkali metal and R⁹¹ is hydrogen, benzyl or benzyl substituted inthe phenyl ring by halogen, C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇-alkylenedioxy, carboxyl or trifluoromethyl; and R^(a), R^(b) and n havethe significance set forth above; or

b) reacting a compound of formula III ##STR4##

wherein R¹¹ is 2- or 4-pyridyl N-oxide and the remaining symbols havethe significance set forth above,

with a trialkylsilyl cyanide and a trialkylamine; or

c) reacting a compound of formula I in which R² is cyano and theremaining symbols have the significance set forth above with an azide inthe presence of an aprotic Lewis acid; or

d) converting a compound of formula I in which R² is cyano and theremaining symbols have the significance set forth above with an alkalimetal alcoholate and thereafter with hydrazine into the correspondingamidrazone and treating this with a nitrite and an acid; or

e) reacting a compound of formula I in which R⁹ is hydrogen with anisocyanate of the formula R¹⁰ NCO; or

f) transforming the cyano group in a compound of formula I in which R²is cyano and the remaining symbols have the significance set forth aboveinto an amidino, carbamoyl, thiocarbamoyl, C₁₋₇ -alkoxycarbonyl,carboxy, hydroxymethyl, formyl or hydroxyamidino group; or

g) alkylating the tetrazolyl group in a compound of formula I in whichR² is tetrazolyl and R⁹ is benzyl, benzyl substituted in the phenyl ringby halogen, C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇ -alkylenedioxy, carboxyl ortrifluoromethyl; and cleaving off a hydroxy protecting group from thereaction product;

and, if desired, converting a compound of formula I obtained into asalt.

The reaction of a compound of formula II with a compound of the formulaMO(CR^(a) R^(b))_(n) OR⁹¹ (process variant a) is conveniently carriedout in a glycol corresponding to this compound as the solvent, e.g. inethylene glycol when n=2 and R^(a) and R^(b) are hydrogen. The alkalimetal M is preferably sodium and Hal is preferably chlorine. Thereaction is conveniently carried out while heating, e.g. to 40-100° C.According to this process variant there are obtained compounds offormula I in which R² signifies cyano and A and B signify CH; or R²signifies hydrogen and one of the symbols A or B signifies N-oxide andthe other signifies CH, and R⁹ is a residue R⁹¹ as defined above, andthe remaining symbols have the given significance.

In process variant b) a N-oxide of formula II is preferably reacted withtrimethylsilyl cyanide and triethylamine. The reaction is convenientlycarried out in acetonitrile while heating to the reflux temperature ofthe reaction mixture. According to this process variant there areobtained compounds of formula I in which R² signifies cyano and one ofthe symbols A or B signifies nitrogen and the other signifies CH and theremaining symbols have the given significance.

In the reaction according to process variant c) there can be used as theazide e.g. sodium azide, guanidinium azide or trimethylsilyl azide.Ammonium salts, e.g. ammonium chloride, can be used as Lewis acids. Thereaction can be carried out in an aprotic, polar solvent such asdimethylformamide or dimethyl sulphoxide, conveniently while heating,e.g. to a temperature of 60-100° C.

The reaction of a compound of formula I in which R² is cyano withhydrazine according to process variant d) proceeds via the iminoether,from which the amidrazone, i.e. a compound corresponding to formula Iwith R² ═--CH(NH)NHNH₂, is obtained with excess hydrazine. Theamidrazone is converted by nitrosation into an iminoazide which cyclizesspontaneously to the tetrazole. According to process variants c) and d)there are obtained compounds of formula I in which R² signifiestetrazolyl and the remaining symbols have the given significance.

The reaction in accordance with process variant e) can be effected in amanner known per se for the preparation of carbamates from alcohols andisocyanates, e.g. in in a suitable anhydrous organic solvent, e.g. ahydrocarbon such as toluene, conveniently while heating. The isocyanatecan be generated in situ, e.g. from an azide of the formula R¹⁰ CON₃ bythermal rearrangement. According to this process variant there areobtained compounds of formula I in which R⁹ signifies a residue--C(O)NHR¹⁰ and the remaining symbols have the given significance.

The transformation of a cyano group R² in a compound of formula I intoan amidino, carbamoyl, thiocarbamoyl, lower-alkoxycarbonyl, carboxy,hydroxymethyl, formyl or hydroxyamidino group in accordance with processvariant f) can be effected in a manner known per se for suchtransformations. For example, the cyano group can be converted bytreatment with alkali alcoholate, e.g. with sodium methylate inmethanol, into an iminoether (i.e., the group C(NH)OCH₃) which can beconverted in situ by treatment with hydrochloric acid into an alkylcarboxylate (e.g. the group --COOCH₃), which can be saponified to thecarboxylic acid by treatment with alcoholic alkali. Alternatively, theiminoether, obtained in situ, can be transformed by treatment withammonium chloride in methanol into the corresponding amidino compound(R² =amidino) and this can be transformed by treatment with aqueousalkali and subsequent acidification into the corresponding carbamoylcompound (R² ═--C(O)NH₂)). By treatment of the iminoether, obtained insitu, with hydroxylamine and aqueous sodium acetate solution there canbe obtained the corresponding hydroxyamidino compounds (R²═--C(NH)NHOH). A carboxy group can be reduced by treatment with reducingagents such as sodium dihydro-bis-(2-methoxyethoxy)aluminate in tolueneto the hydroxymethyl group and this can be oxidized to the formyl groupby treatment with oxidizing agents such as manganese dioxide. In thesereaction sequences R³ should not contain a hydroxy group, i.e. R⁹ shouldnot represent hydrogen, but should represent e.g. benzyl.

The alkylation of a compound of formula I in accordance with processvariant g) can be carried out in a manner known per se, e.g. bytreatment with a lower-alkyl halide in the presence of a base such as Ktert.-butylate in tetrahydrofuran, whereby a thus-obtained mixture of1 - and 2-lower-alkyl-tetrazolyl compounds of formula I can be separatedin a manner known per se, e.g. by chromatography. Suitable hydroxyprotecting groups are e.g. alkylsilyl protecting groups such asdimethyl-tert.-butylsilyl and tetrahydropyranyl, which can be introducedand cleaved off from the reaction product in a manner known per se.According to process variant g) there are accordingly obtained compoundsof formula I in which R² represents a lower-alkyl-tetrazolyl residue andR⁹ represents hydrogen.

The compounds of formula I which contain a carboxy or tetrazolyl groupcan be converted in a manner known per se into pharmaceutically usablesalts, e.g. alkali salts such as Na and K salts or alkaline earth metalsalts such as Ca or Mg salts or salts with amines such asmonoethanolamine.

The compounds which are used as starting materials, insofar as they arenot known or their preparation is described hereinafter, can be preparedin analogy to known methods or to methods described below.

The compounds of formula I given above are endothelin receptorinhibitors. They can therefore be used for the treatment of disorderswhich are associated with endothelin activities, especially circulatorydisorders such as hypertension, ischaemia, vasospasms and anginapectoris.

The inhibitory activity of the compounds of formula I on endothelinreceptors can be demonstrated using the test procedures describedhereinafter:

I: Inhibition of endothelin binding to recombinant ET_(A) receptors

A cDNA coding for human ET_(A) receptors of human placenta was cloned(M. Adachi, Y. -Y. Yang, Y. Furuichi and C. Miyamoto, BBRC 180,1265-1272) and expressed in the baculovirus-insect cell system.Baculovirus-infected insect cells from a 23 l fermenter are centrifugedoff (3000×g, 15 minutes, 4° C.) 60 hours after the infection,re-suspended in Tris buffer (5 mM, pH 7.4, 1 mM MgCl₂) and againcentrifuged. After a further re-suspension and centrifugation the cellsare suspended in 800 ml of the same buffer and freeze-dried at -120° C.The cells disintegrate when the suspension in this hypotonic buffermixture is thawed. After a repeated freeze-drying/thawing cycle thesuspension is homogenized and centrifuged (25000×g, 15 minutes, 4° C.).After suspension in Tris buffer (75 mM, pH 7.4, 25 mM MgCl₂, 250 mMsucrose) 1 ml aliquots (protein content about 3.5 mg/ml) are stored at-85° C.

For the binding assay, the freeze-dried membrane preparations are thawedand, after centrifugation at 20° C. and 25000 g for 10 minutes,re-suspended in assay buffer (50 mM Tris buffer, pH 7.4, containing 25mM MnCl₂, 1 mM EDTA and 0.5% bovine serum albumin). 100 μl of thismembrane suspension containing 70 μg of protein are incubated with 50 μlof ¹²⁵ I-endothelin (specific activity 2200 Ci/mMol) in assay buffer(25000 cpm, final concentration 20 pM) and 100 μl of assay buffercontaining varying concentrations of test compound. The incubation iscarried out at 20° C. for 2 hours or at 4° C. for 24 hours. Theseparation of free and membrane-bound radio-ligands is carried out byfiltration over a glass fibre filter. The inhibitory activity ofcompounds of formula I determined in this test procedure is given inTable 1 as the IC₅₀, i.e. as the concentration [nM] which is required toinhibit 50% of the specific binding of ¹²⁵ I-endothelin.

                  TABLE 1                                                         ______________________________________                                        Compound of Example                                                                            IC.sub.50 [nM]                                               ______________________________________                                         4               6                                                              29 4                                                                          35 2                                                                          36 8                                                                          40 8                                                                          41 1                                                                        ______________________________________                                    

II. Inhibition of endothelin-induced contractions in isolated rat aortarings

Rings with a length of 5 mm were cut out from the thorax aorta of adultWistar-Kyoto rats. The endothelium was removed by lightly rubbing theinternal surface. Each ring was immersed at 37° C. in 10 ml ofKrebs-Henseleit solution in an isolated bath while gassing with 95% O₂and 5% CO₂. The isometric stretching of the rings was measured. Therings were stretched to a pre-tension of 3 g. After incubation for 10minutes with the test compound or vehicle cumulative dosages ofendothelin-1 were added. The activity of the test compound wasascertained by the observed shift to the right of the dosage-activitycurve of endothelin-1 in the presence of different concentrations ofantagonist. This shift to the right (or "dose ratio", DR) corresponds tothe quotient from the EC₅₀ values of endothelin-1 in the presence and inthe absence of antagonist, with the EC₅₀ value denoting the endothelinconcentration required for a half-maximum contraction.

The corresponding pA₂ value, which is a measure of the activity of thetest compound, was calculated using a computer programme according tothe following equation from the "dose ratio" DR for each individualdosage-activity curve.

pA₂ =log(DR-1)-log(antagonist-concentration)

The EC₅₀ of endothelin in the absence of test compounds is 0.3 nM.

The pA₂ values obtained with compounds of formula I are given in Table2.

                  TABLE 2                                                         ______________________________________                                                        Dose ratio                                                      Compound of Example (switch to the right)                                   ______________________________________                                         4              9.60                                                            29 10.0                                                                       35 9.5                                                                        36 9.4                                                                        40 10.2                                                                       41 10.6                                                                     ______________________________________                                    

On the basis of their capability of inhibiting endothelin binding, thecompounds of formula I can be used as medicaments for the treatment ofdisorders which are associated with vasoconstriction of increasingfrequencies. Examples of such disorders are high blood pressure,coronary disorders, cardiac insufficiency, renal and myocardialischaemia, renal insufficiency, dialysis, cerebral ischaemia, cerebralinfarct, migraine, subarachnoid haemorrhage, Raynaud syndrome andpulmonary high pressure. They can also be used in atherosclerosis, theprevention of restenosis after balloon-induced vascular dilation,inflammations, gastric and duodenal ulcers, ulcus cruris, gram-negativesepsis, shock, glomerulonephtritis, renal colic, glaucoma, asthma, inthe therapy and prophylaxis of diabetic complications and complicationsin the administration of cyclosporin, as well as other disordersassociated with endothelin activities.

The compounds of formula I can be administered orally, rectally,parentally, e.g. intravenously, intramuscularly, subcutaneously,intrathecally or transdermally; or sublingually or as opththalmologicalpreparations, or as an areosol. Capsules, tablets, suspensions orsolutions for oral administration, suppositories, injection solutions,eye drops, salves or spray solutions are examples of administrationforms.

Intravenous, intramuscular or oral administration is a preferred form ofuse. The dosages in which the compounds of formula I are administered ineffective amounts depend on the nature of the specific activeingredient, the age and the requirements of the patient and the mode ofadministration. In general, dosages of about 0.1-100 mg/kg body weightper day come into consideration. The preparations containing thecompounds of formula I can contain inert or also pharmacodynamicallyactive additives. Tablets or granulates e.g. can contain a series ofbinders, fillers, carriers or diluents. Liquid preparations can bepresent, for example, in the form of a sterile water-miscible solution.Capsules can contain a filler or thickener in addition to the activeingredient. Furthermore, flavour-improving additives as well assubstances usually used as preserving, stabilizing, moisture-retainingand emulsifying agents as well as salts for varying the osmoticpressure, buffers and other additives can also be present.

The previously mentioned carrier materials and diluents can compriseorganic or inorganic substances, e.g. water, gelatine, lactose, starch,magnesium stearate, talc, gum arabic, polyalkylene glycols and the like.It is a prerequisite that all adjuvants used in the manufacture of thepreparations are non-toxic.

The following Examples illustrate the invention in more detail. DMFdenotes dimethylformamide, THF denotes tetrahydrofuran and EtOAc denotesethyl acetate.

EXAMPLE 1

a) 200 ml of dimethoxyethane and 110.9 g of4-[4-(4-tert-butyl-phenyl-sulphonylamino)-6-chloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine1-oxide are added all at once to a solution of 23.80 g of sodium in 660ml of ethylene glycol. The solution is heated at 90° C. for 20 hourswhile stirring, thereafter cooled, poured into 2500 ml of H₂ O andthereafter treated with CH₃ COOH to pH 5. The mixture is extracted threetimes with EtOAc, the organic phase is washed with H₂ O, dried with Na₂SO₄ and evaporated under reduced pressure. The residue is recrystallizedfrom CH₃ CN and thereafter twice from a mixture of acetone and CH₃ CN.There is thus obtained4-[4-(4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine1-oxide.

Preparation of the starting material:

b) 53.1 g of 4-cyano-pyridine (98%) are added all at once to a solutionof 1.15 g of sodium in 200 ml of abs. MeOH. After 6 hours 29.5 g of NH₄Cl are added while stirring vigorously. The mixture is stirred at roomtemperature overnight. 600 ml of ether are added thereto, whereupon theprecipitate is filtered off under suction and thereafter dried at 50° C.under reduced pressure. There is thus obtained 4-amidino-pyridinehydrochloride (decomposition point 245-247° C.).

c) 112.9 g of diethyl (2-methoxyphenoxy)malonate are added dropwisewithin 30 minutes to a solution of 27.60 g of sodium in 400 ml of MeOH.Thereafter, 74.86 g of the amidine hydrochloride obtained in b) areadded all at once. The mixture is stirred at room temperature overnightand evaporated at 50° C. under reduced pressure. The residue is treatedwith 500 ml of ether and filtered off under suction. The filter cake isdissolved in 1000 ml of H₂ O and treated little by little with 50 ml ofCH₃ COOH. The precipitate is filtered off under suction, washed with 400ml of H₂ O and dried at 80° C. under reduced pressure. There is thusobtained 5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidine-4,6-diol (ortautomer), melting point above 250° C.

d) A suspension of 154.6 g of5-(2-methoxy-phenoxy)-2-(pyridin-4-yl)-pyrimidine-4,6-diol (or tautomer)in 280 ml of POCl₃ is heated at 120° C. in an oil bath for 24 hourswhile stirring vigorously. The reaction mixture changes gradually into adark brown liquid which is evaporated under reduced pressure andthereafter taken up three times with 500 ml of toluene and evaporated.The residue is dissolved in 1000 ml of CH₂ Cl₂, treated with ice and H₂O and thereafter adjusted with 3N NaOH until the aqueous phase has pH 8.The organic phase is separated and the aqueous phase is extracted twicewith CH₂ Cl₂. The combined CH₂ Cl₂ extracts are dried with MgSO₄,evaporated to half of the volume, treated with 1000 ml of acetone andthe CH₂ Cl₂ remaining is distilled off at normal pressure. Afterstanding in a refrigerator for 2 hours the crystals are filtered offunder suction and dried at 50° C. overnight. There is thus obtained4,6-dichloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl)-pyrimidine, meltingpoint 178-180° C.

e) A solution of 17.4 g of4,6-dichloro-5-(2-methoxyphenoxy)-2-pyridin-4-yl)-pyrimidine in 100 mlof CH₃ CN is boiled at reflux for 3 hours with 15 ml of a 32% peraceticacid solution, thereafter cooled and stored in a refrigerator overnight.The crystals are filtered off under suction and dried at 50° C. underreduced pressure. There is thus obtained4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine 1-oxide,melting point 189-190° C.

f) A solution of 36.4 g of4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine 1-oxideand 52.8 g of p-tert-butylphenyl-sulphonamide potassium in 150 ml ofabs. DMF is stirred at room temperature for 24 hours. Thereafter, it ispoured into a mixture of 1500 ml of H₂ O and 1000 ml of ether whilestirring mechanically, whereby a precipitate forms. The suspension isadjusted to pH 5 with CH₃ COOH, suction filtered, the crystals arewashed with cold water and thereafter with ether and dried at 50° C.There is thus obtained4-[4-(4-tert-butyl-phenylsulphonylamino)-6-chloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine1-oxide as a colourless material of melting point 247-249° C.

EXAMPLE 2

A solution of 78.45 g of4-[4-(4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine1-oxide, 122.5 g of trimethylsilyl cyanide, 127.8 g of triethylamine and1200 ml of CH₃ CN is boiled at reflux for 20 hours and thereafterevaporated under reduced pressure. The oily residue is taken up in 1000ml of EtOAc and the solution is washed with CH₃ COOH:H₂ O 9:1 and thenwith H₂ O. The EtOAc extracts are dried with Na₂ SO₄. After evaporationof the solvent the residue is taken up in a mixture of CH₃ CN and CF₃COOH (20:1), whereby a crystalline precipitate separates. There is thusobtained4-tert-butyl-N-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamideof melting point 176-179° C.

EXAMPLE 3

A suspension of 50.0 g of4-tert-butyl-N-[2-(2-cyanopyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide,46.33 g of NH₄ Cl and 56.47 g of NaN₃ in 1600 ml of DMF is heated to 70°C. for 24 hours while stirring vigorously. The majority of the solventis distilled off under reduced pressure, the residue is dissolved in H₂O, the solution is extracted four times at pH 6.5 with ether, thereaftertreated with CH₃ COOH to pH=4.5 and extracted with EtOAc. After workingup there is obtained a residue which is treated with ether and filteredoff under suction therefrom. There is thus obtained4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide,melting point 225-227° C.

EXAMPLE 4

a) To a solution, heated to 90° C., of 46.0 g of4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamidein 600 ml of abs. dioxan is added dropwise within 60 minutes whilestirring a cold solution of 22.0 g of 2-pyridylcarbonyl azide in 200 mlof dioxan. After 4 hours the solvent is evaporated under reducedpressure, the residue is taken up in 300 ml of EtOAc and left to standat room temperature overnight. The crystalline mass is filtered offunder suction and washed with EtOAc. After repeated recrystallizationfrom tetrahydrofuran and EtOAc and drying under reduced pressure firstlyat 45° C. for 3 days and thereafter at 65° C. for a further 2 days thereis obtained2-[6-(4-tert-butyl-phenylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl-oxy]-ethylpyridin-2-ylcarbamate, melting point from 214° C. with very slowdecomposition.

b) The 2-pyridyl-carbonyl azide used as the starting material can beprepared as follows:

A solution of 53.9 g of 2-picolinic acid in 330 ml of abs. DMF and 61.2ml of triethylamine is treated dropwise within 30 minutes at 10° C. with99.7 ml of diphenylphosphoryl azide. After 2 hours at room temperaturethe solution is evaporated for the most part at 30° C. under reducedpressure, the oily residue is treated with 200 ml of a 5% sodiumbicarbonate solution and exhaustively extracted with ether. The etherealextracts are combined, dried with MgSO₄ and evaporated at roomtemperature under reduced pressure. The yellowish oily residue is cooledin an ice bath at 0-5° C. and the crystals are washed at -20° C. with a1:1 mixture of ether and hexane. There is thus obtained2-pyridylcarbonyl azide as colourless crystals of melting point 39-41°C.

EXAMPLE 5

A solution of 47.8 g of2-[6-(4-tert-butyl-phenylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate in 500 ml of abs. THF is treated dropwise with acold solution of 2.8 g of sodium in 50 ml of methanol, whereby thereforms gradually a solid precipitate which, after stirring at roomtemperature for 1 hour, is filtered off under suction, dried undergreatly reduced pressure at 35° C. for 3 days and thereafter at 50° C.for 2 days. There is thus obtained the bis-sodium salt, decompositionpoint above 250° C.

EXAMPLE 6

The same tetrazole as in Example 3 is obtained starting from the samestarting material as in Example 3 in a one-pot reaction (3 steps) underthe following conditions:

2.4 ml of a 1.0N sodium methylate solution are added at room temperatureto a suspension of 1.15 g (2 mmol) of4-tert-butyl-N-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamidein 50 ml of abs. MeOH. The clear yellowish solution which resultstherefrom is held at 40° C. for 3 days.

The solution of the iminoether is slowly added dropwise at roomtemperature within 30 minutes to a suspension of 302 mg (4.4 mmol) of H₂N--NH₂ ·HCl in 10 ml of abs. MeOH, whereby a crystalline precipitateseparates gradually. The suspension is cooled to 2° C. while stirringfurther and treated with 15 ml of 1.0N HCl. The clear yellowish solution(pH=1.7) is treated dropwise with a solution of 800 mg (11.6 mmol) ofNaNO₂ in 10 ml of H₂ O in such a manner that the temperature does notexceed 5° C. (pH 2.7). After 1 hour a further 2 ml of 1N HCl are addedand then a solution of 200 mg (2.9 mmol) of NaNO₂ in 2 ml of H₂ O isadded. The solution is left at room temperature for 2 hours, the MeOH isevaporated under reduced pressure and the suspension remaining behind isextracted with EtOAc. The combined EtOAc solutions are firstly washedtwice with H₂ O and thereafter carefully extracted with a 0.5N NaHCO₃--H₂ O solution. The combined aqueous (NaHCO₃) solutions are carefullytreated with 3N HCl (to pH=2) and the suspension is extracted with EtOAcas usual. After evaporation of the solvent under reduced pressure thereis obtained a crystalline residue which is identical with the productobtained in Example 3.

EXAMPLE 7

a) In analogy to Example 1a), fromN-[6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamideand Na glycolate in ethylene glycol there is obtainedN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide,melting point 110-112° C. (from EtOAc).

b) In analogy to Example 2, fromN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamidethere is obtainedN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxyphenoxy)-pyrimidin-4-yl]-benzenesulphonamide.

EXAMPLE 8

a) In analogy to Example 1a), fromN-[6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-4-methyl-benzenesulphonamidethere is obtained N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-4-methyl-benzenesulphonamide, meltingpoint 172-173° C. (from EtOAc).

b) In analogy to Example 2, fromN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-4-methyl-benzenesulphonamidethere is obtainedN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-methyl-benzenesulphonamide.

EXAMPLE 9

a) In analogy to Example 1a), fromN-[6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-4-methoxy-benzenesulphonamidethere is obtainedN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-4-methoxy-benzenesulphonamideas a white solid.

b) In analogy to Example 2, fromN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-4-methoxy-benzenesulphonicacid there is obtainedN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-methoxy-benzenesulphonamide.

EXAMPLE 10

a) In analogy to Example 1a), fromN-[6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-4-methylsulphanyl-benzenesulphonamidethere is obtainedN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-4-methylsulphanyl-benzenesulphonamide,melting point 146-150° C. (from acetonitrile).

b) In analogy to Example 2, fromN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-4-methylsulphanyl-benzenesulphonamidethere is obtainedN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-methylsulphanyl-benzenesulphonamide.

EXAMPLE 11

a) In analogy to Example 1a), from 1,3-benzodioxol-5-sulphonic acid6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamidethere is obtained 1,3-benzodioxol-5-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamide,melting point 174-175° C. (from acetonitrile).

b) In analogy to Example 2, from 1,3-benzodioxol-5-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamidethere is obtained 1,3-benzodioxol-5-sulphonic acid2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamide.

EXAMPLE 12

a) In analogy to Example 1a), fromN-[6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-3,4-dimethoxy-benzenesulphonamidethere is obtainedN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-3,4-dimethoxy-benzenesulphonamide,melting point 189-191° C. (from EtOAc).

b) In analogy to Example 2, fromN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-3,4-dimethoxy-benzenesulphonamidethere is obtainedN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-3,4-dimethoxy-benzenesulphonamide.

EXAMPLE 13

a) In analogy to Example 1a), fromN-[6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-2,5-dimethoxy-benzenesulphonamidethere is obtainedN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-2,5-dimethoxy-benzenesulphonamideas a white solid.

b) In analogy to Example 2, fromN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-2,5-dimethoxy-benzenesulphonamidethere is obtainedN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-2,5-dimethoxy-benzenesulphonamide.

EXAMPLE 14

a) In analogy to Example 1a), from pyridine-3-sulphonic acid6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamidethere is obtained pyridine-3-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamide,melting point 227-228° C. (from EtOAc).

b) In analogy to Example 2, from pyridine-3-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamidethere is obtained pyridine-3-sulphonic acid2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamide.

EXAMPLE 15

a) In analogy to Example 1a), from 5-methyl-pyridine-2-sulphonic acid6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamidethere is obtained 5-methyl-pyridine-2-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamide,melting point 188-190° C. (from acetonitrile).

b) In analogy to Example 2, from 5-methyl-pyridine-2-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamidethere is obtained 5-methyl-pyridine-2-sulphonic acid2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamide.

EXAMPLE 16

a) In analogy to Example 1a), from 5-isopropyl-pyridine-2-sulphonic acid6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamidethere is obtained 5-iso-propyl-pyridine-2-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamide,melting point 140-141° C. (from EtOAc).

b) In analogy to Example 2, from 5-isopropyl-pyridine-2-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamidethere is obtained 5-isopropyl-pyridine-2-sulphonic acid2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamide.

EXAMPLE 17

a) In analogy to Example 1a), from4-tert-butyl-N-[6-chloro-5-(2-chloro)-5-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamidethere is obtained4-tert-butyl-N-[5-(2-chlor-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide,melting point 228-230° C. (from EtOAc).

b) In analogy to Example 2, from4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamidethere is obtained4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-benzenesulphonamide.

EXAMPLE 18

a) In analogy to Example 1a), from 1,3-benzodioxol-4-sulphonic acid6-chloro-5-(2-chloro-5-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamidethere is obtained 1,3-benzodioxol-4-sulphonic acid5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamide,melting point 208-210° C. (from EtOAc).

b) In analogy to Example 2, from 1,3-benzodioxol-4-sulphonic acid5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamidethere is obtained 1,3-benzodioxol-5-sulphonic acid5-(2-chloro-5-methoxy-phenoxy)-2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-ylamide.

EXAMPLE 19

a) In analogy to Example 1a), from 5-isopropyl-pyridine-2-sulphonicacid-6-chloro-5-(2-chloro-5-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamidethere is obtained 5-l isopropyl-pyridine-2-sulphonicacid-5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamide,melting point 204-206° C. (from EtOAc).

b) In analogy to Example 2 from 5-isopropyl-pyridine-2-sulphonic acid5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamidethere is obtained 5-isopropyl-pyridine-2-sulphonic acid5-(2-chloro-5-methoxy-phenoxy)-2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-ylamide.

EXAMPLE 20

a) In analogy to Example 1a), from2-[4-(4-tert-butyl-phenylsulphonylamino)-6-chloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine1-oxide there is obtained2-[4-(4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine1-oxide as an amorphous substance.

b) In analogy to Example 2 from2-[4-(4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine1-oxide there is obtained4-tert-butyl-N-[2-(6-cyano-pyridin-2-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide.

EXAMPLE 21

In analogy to Example 3, fromN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamidethere is obtainedN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamideas a white substance of melting point 205-207° C. from acetonitrile.

EXAMPLE 22

In analogy to Example 3, fromN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-methyl-benzenesulphonamidethere is obtainedN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-4-methyl-benzenesulphonamideas a white substance of melting point 214-216° C. from CH₃ CN.

EXAMPLE 23

In analogy to Example 3, fromN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-methoxy-benzenesulphonamidethere is obtainedN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-4-methoxy-benzenesulphonamideas a white substance of melting point 218-220° C. from acetonitrile.

EXAMPLE 24

In analogy to Example 3, fromN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-methylsulphanyl-benzenesulphonamidethere is obtainedN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-4-methylsulphanyl-benzene-sulphonamideas a white substance.

EXAMPLE 25

In analogy to Example 3, from 1,3-benzodioxol-5-sulphonic acid2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamidthere is obtained 1,3-benzodioxol-5-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamideas a white substance of melting point 227-229° C. from CH₃ CN.

EXAMPLE 26

In analogy to Example 3, fromN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-3,4-dimethoxy-benzenesulphonamidethere is obtainedN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-3,4-dimethoxy-benzenesulphonamideas a white substance of melting point 224-225° C. from acetonitrile.

EXAMPLE 27

In analogy to Example 3, fromN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-2,5-dimethoxy-benzenesulphonamidethere is obtainedN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-2,5-dimethoxy-benzenesulphonamideas a white substance.

EXAMPLE 28

In analogy to Example 3, from pyridine-3-sulphonic acid2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamidethere is obtained pyridine-3-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamideas a white substance.

EXAMPLE 29

In analogy to Example 3, from 5-methyl-pyridine-2-sulphonic acid2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamidethere is obtained 5-methyl-pyridine-2-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamideas a white substance of melting point 239-241° C. from CH₃ CN.

EXAMPLE 30

In analogy to Example 3, from 5-isopropyl-pyridine-2-sulphonic acid2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamidethere is obtained 5-isopropyl-pyridine-2-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamideas a white substance of melting point 198-200° C. from acetonitrile. Thecorresponding disodium salt is obtained as a white powder from thisproduct using sodium methylate in analogy to Example 5.

EXAMPLE 31

In analogy to Example 3, from4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-[2-(2-cyano-pyridin-4-yl]-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-benzenesulphonamidethere is obtained4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamideof melting point 170-172° C. from CH₃ CN. The corresponding disodiumsalt is obtained as a white powder from this product using sodiummethylate in analogy to Example 5.

EXAMPLE 32

In analogy to Example 3, from 1,3-benzodioxol-5-sulphonic acid5-(2-chloro-5-methoxy-phenoxy)-2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-ylamidethere is obtained 1,3-benzodioxol-5-sulphonic acid[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-amide.

EXAMPLE 33

In analogy to Example 3, from 5-isopropyl-pyridine-2-sulphonic acid5-(2-chloro-5-methoxy-phenoxy)-2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-ylamidethere is obtained 5-isopropyl-pyridine-2-sulphonic acid[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-amide.

EXAMPLE 34

In analogy to Example 3, from4-tert-butyl-N-[2-(6-cyano-pyridin-2-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamidethere is obtained4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[6-(1H-tetrazol-5-yl)-pyridin-2-yl]-pyrimidin-4-yl]-benzene-sulphonamideof melting point 248-251° C. (with decomposition) from CH₂ Cl₂ +CH₃ CN.

EXAMPLE 35

In analogy to Example 4, fromN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamideand 2-pyridyl-carbonyl azide there is obtained2-[5-(2-methoxy-phenoxy)-6-phenyl-sulphonylamino-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate as a white substance.

EXAMPLE 36

In analogy to Example 4, fromN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-4-methyl-benzenesulphonamideand 2-pyridylcarbonyl azide there is obtained2-[5-(2-methoxy-phenoxy)-6-(4-methyl-phenylsulphonylamino)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate as a white substance of melting point 224-225° C.from CH₃ CN.

EXAMPLE 37

In analogy to Example 4, fromN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-4-methyl-benzenesulphonamideand 3,4-methylenedioxy-phenyl-carbonyl azide there is obtained2-[5-(2-methoxy-phenoxy)-6-(4-methylphenylsulphonylamino)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl1,3-benzodioxol-5-ylcarbamate of melting point 198-199° C. from CH₃ CN.

EXAMPLE 38

In analogy to Example 4, fromN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-4-methoxy-benzenesulphonamideand 2-pyridylcarbonyl azide there is obtained2-[5-(2-methoxy-phenoxy)-6-(4-methoxy-phenylsulphonylamino-2-(2-1H-tetrazol-5-yl-pyridin-2-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate of melting point 224-225° C. from EtOAc.

EXAMPLE 39

In analogy to Example 4, fromN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-4-methoxy-benzenesulphonamideand 3,4-methylenedioxy-phenylcarbonyl azide there is obtained2-[5-(2-methoxy-phenoxy)-6-(4-methoxy-phenylsulphonylamino)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl1,3-benzodioxol-5-ylcarbamate of melting point 198-200° C. from EtOAc.

EXAMPLE 40

In analogy to Example 4, fromN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-4-methylsulphanyl-benzenesulphonamideand 2-pyridylcarbonyl azide there is obtained2-[5-(2-methoxy-phenoxy)-6-(4-methylsulphanylphenylsulphonylamino)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.

EXAMPLE 41

In analogy to Example 4, from 1,3-benzodioxol-5-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamideand 2-pyridylcarbonyl azide there is obtained2-[6-(1,3-benzodioxol-5-yl-sulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate of melting point 194-196° C. from EtOAc.

EXAMPLE 42

In analogy to Example 4, from 1,3-benzodioxol-5-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamideand 3,4-methylenmdioxy-phenyl-carbonyl azide there is obtained2-[6-(1,3-benzodioxol-5-ylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl1,3-benzodioxol-5-ylcarbamate of melting point 187-188° C. from EtOAc.

EXAMPLE 43

In analogy to Example 4, fromN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-3,4-dimethoxy-benzenesulphonamideand 2-pyridylcarbonyl azide there is obtained2-[6-(3,4-dimethoxy-phenylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.

EXAMPLE 44

In analogy to Example 4, fromN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-2,5-dimethoxy-benzenesulphonamideand 2-pyridylcarbonyl azide there is obtained2-[5-(2-methoxy-phenoxy)-6-(2,5-dimethoxy-phenylsulphonylamino)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-2-yloxy]-ethylpyridin-2-ylcarbamate.

EXAMPLE 45

In analogy to Example 4, from pyridine-3-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamideand 2-pyridylcarbonyl azide there is obtained2-[5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-6-pyridin-3-ylsulphonylamino-pyrimidin4-yloxy]-ethylpyridin-2-ylcarbamate.

EXAMPLE 46

In analogy to Example 4, from pyridine-3-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamideand 3,4-methylenedioxy-phenyl-carbonyl azide there is obtained2-[5-(2-methoxy-phenoxy)-6-pyridin-3-ylsulphonylamino-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl1,3-benzodioxol-5-ylcarbamate.

EXAMPLE 47

In analogy to Example 4, from 5-methyl-pyridine-2-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamideand 2-pyridylcarbonyl azide there is obtained2-[5-(2-methoxy-phenoxy)-6-(5-methyl-pyridin-2-ylsulphonylamino)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.

EXAMPLE 48

In analogy to Example 4 from 5-isopropyl-pyridine-2-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamideand 2-pyridylcarbonyl azide there is obtained2-[6-(5-isopropyl-pyridin-2-ylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.

EXAMPLE 49

In analogy to Example 4, from 5-isopropyl-pyridine-2-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamideand 3,4-methylenedioxy-phenyl-carbonyl azide there is obtained2-[6-(5-isopropyl-pyridin-2-ylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl1,3-benzodioxol-5-ylcarbamate.

EXAMPLE 50

In analogy to Example 4, from4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamideand 2-pyridylcarbonyl azide there is obtained2-[6-(4-tert-butyl-phenylsulphonylamino)-5-(2-chloro-5-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.

EXAMPLE 51

In analogy to Example 4, from 1,3-benzodioxol-5-sulphonic acid[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-amideand 2-pyridylcarbonyl azide there is obtained2-[6-(1,3-benzodioxol-5-ylsulphonylamino)-5-(2-chloro-5-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.

EXAMPLE 52

In analogy to Example 4, from 5-isopropyl-pyridine-2-sulphonic acid[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-amidethere is obtained2-[5-(2-chloro-5-methoxy-phenoxy)-6-(5-isopropyl-pyridin-2-ylsulphonylamino]-2-(2-1H-tetrazol-5-yl-pyridin-2-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-yl-carbamate.

EXAMPLE 53

In analogy to Example 4, from4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[6-(1H-tetrazol-5-yl)-pyridin-2-yl]-pyrimidin-4-yl]-benzenesulphonamidethere is obtained2-[6-(4-tert-butyl-phenylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-2-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.

EXAMPLE 54

In analogy to Example 1, from benzyloxy-ethanol Na with4-[4-(4-tert-butyl-phenylsulphonylamino)-6-chloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine1-oxide there is obtainedN-[6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphonamideof melting point 170-171° C. from CH₃ CN and therefrom withtri-methylsilyl cyanide in boiling triethylamine in analogy to Example1, paragraph a), there is obtainedN-[6-(2-benzyloxy-ethoxy)-2-(2-cyano-pyridin-4-yl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphonamide.

EXAMPLE 55

In analogy to Example 3, fromN-[6-(2-benzyloxy-ethoxy)-2-(2-cyano-pyridin-4-yl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphonamidethere is obtainedN-[6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphonamideas an amorphous substance of melting point 173-175° C.

EXAMPLE 56

In analogy to Example 1, from benzyloxy-ethanol sodium and5-methyl-pyridine-2-sulphonic acid6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamidethere is obtained 5-methyl-pyridine-2-sulphonic acid[6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-amide,melting point 206-208° C. from CH₃ CN, and therefrom with trimethylsilylcyanide in boiling triethylamine in analogy to Example 2 there isobtained the corresponding nitrile, 5-methylpyridine-2-sulphonicacid-N-[6-(2-benzyloxy-ethoxy)-2-(2-cyanopyridin-4-yl)-5-(2-methoxyphenoxy)-pyrimidin-4-yl]-amide.

EXAMPLE 57

In analogy to Example 3, from the nitrile of Example 56 there isobtained 5-methyl-pyridine-2-sulphonic acid[6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl]-amide,melting point 202-204° C. from CH₃ CN.

EXAMPLE 58

In analogy to Example 1, from benzyloxy-ethanol sodium and5-isopropyl-pyridine-2-sulphonic acid6-chloro-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-ylamidethere is obtained 5-isopropyl-pyridine-2-sulphonic acid[6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(1-oxy-pyridin-4-yl)-pyrimidin-4-yl]-amideand therefrom with trimethylsilyl cyanide in boiling triethylamine inanalogy to Example 2 there is obtained the corresponding nitrile,5-isopropylpyridine-2-sulphonic acidN-[6-(2-benzyloxy-ethoxy)-2-(2-cyanopyridin-4-yl)-5-(2-methoxyphenoxy)-pyrimidin-4-yl]-amide.

EXAMPLE 59

In analogy to Example 3, from4-isopropyl-N-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]benzenesulphonamidethere is obtained 5-iso-propyl-pyridine-2-sulphonic acid[6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl]-amideof melting point 236-237° C. from CH₃ CN.

EXAMPLE 60

In analogy to Example 6, from4-tert-butyl-N-[2-(2-cyanopyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamidethere is obtained the coresponding iminoether and therefrom with NH₄ Clin CH₃ OH at room temperature there is obtained4-tert-butyl-N-[2-[2-(amino-imino-methyl)-pyridin-4-yl]-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide.

EXAMPLE 61

In analogy to Example 6, from4-tert-butyl-N-[2-(2-cyanopyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamidethere is obtained the corresponding iminoether and therefrom with NH₂OH·HCl in CH₃ OH at room temperature there is obtained4-tert-butyl-N-[2-[2-(hydroxyamino-imino-methyl)-pyridin-4-yl]-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzene-sulphonamide.

EXAMPLE 62

In analogy to Example 6, from4-tert-butyl-N-[2-(2-cyanopyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamidethere is obtained the corresponding iminoether and therefrom with 3N HClat room temperature there is obtained ethyl4-[4-(4-tert-butyl-phenyl-sulphonylamino)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboxylate.

EXAMPLE 63

By treating the ester prepared in Example 62 with 1N methanolic sodiumhydroxide solution at room temperature and acidifying the reactionsolution with acetic acid there is obtained the corresponding4-[4-(4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboxylicacid.

EXAMPLE 64

a) In analogy to Example 1, from4-tert.-butyl-N-[6-chloro-2-(3-cyano-phenyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamideand ethylene glycol sodium salt there is obtained4-tert.-butyl-N-[2-(3-cyano-phenyl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzene-sulphonamideas a white product of melting point 197-198° C. from EtOAc.

Preparation of the starting material:

In analogy to Example 1 b), from 1,3-dicyanobenzene and sodium methylatein methanol followed by ammonium chloride there is obtained3-cyano-benzamidine hydrochloride and therefrom with diethyl(2-methoxy-phenoxy)malonate there is obtainedrac.-3-[5-(2-methoxy-phenoxy)-4,6-dioxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-benzonitrileas a white product. From this compound with PCl₅ and POCl₃ there isobtained3-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-benzonitrile witha melting point of 155-156° from EtOAc. Reaction with4-tert.-butylbenzenesulphonamide K yields4-tert.-butyl-N-[6-chloro-2-(3-cyanophenyl)-5-(2-methoxyphenoxy)-pyrimidin-4-yl]-benzenesulphonamide.

EXAMPLE 65

In analogy to Example 3, from4-tert.-butyl-N-[2-(3-cyanophenyl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide,sodium azide and ammonium chloride in DMF there is obtained4-tert.-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(3-1H-tetrazol-5-yl-phenyl)-pyrimidin-4-yl]-benzenesulphonamideas a solid.

EXAMPLE 66

In analogy to Example 4, from4-tert.-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(3-1H-tetrazol-5-yl-phenyl)-pyrimidin-4-yl]-benzenesulphonamideand α-pyridylcarbonyl azide there is obtained2-[6-(4-tert.-butyl-phenyl-sulphonyl)-5-(2-methoxy-phenoxy)-2-(3-1H-tetrazol-5-yl-phenyl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate of melting point 138-139° C.

EXAMPLE 67

In analogy to Example 1, from4-tert.-butyl-N-[6-chloro-2-(3-cyano-phenyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamideand benzyloxy-ethanol sodium salt there is obtainedN-[6-(2-benzyloxy-ethoxy)-2-(3-cyano-phenyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert.-butyl-benzene-sulphonamideas a solid material of melting point 120-122° C. from EtOAc.

EXAMPLE 68

In analogy to Example 3, fromN-[6-(2-benzyloxy-ethoxy)-2-(3-cyano-phenyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert.-butyl-benzenesulphonamide,sodium azide and ammonium chloride in DMF there is obtainedN-[6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(3-1H-tetrazol-5-yl-phenyl)-pyrimidin-4-yl]-4-tert.-butyl-benzenesulphonamideas a lighy yellow foam.

EXAMPLE 69

In analogy to Example 1, from4-tert.-butyl-N-[6-chloro-2-(4-cyano-phenyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamideand ethylene glycol sodium salt there is obtained4-tert.-butyl-N-[2-(4-cyano-phenyl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzene-sulphonamideas a light brownish material of melting point 169-170° C. from EtOAc.

Preparation of the starting material:

From 1,4-dicyanobenzene and sodium methylate in methanol followed byammonium chloride there is obtained 4-cyano-benzamidine hydrochloride,which is used in the next step without further purification, andtherefrom with diethyl (2-methoxy-phenoxy)-malonate there is obtainedrac.-4-[5-(2-methoxy-phenoxy)-4,6-dioxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-benzo-nitrileas a yellow product with a melting point >250° C. With PCl₅ and POCl₃this compound yields4-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-benzonitrile as abrownish material of melting point 179-180° C. from EtOAc. Reaction with4-tert.-butyl-benzenesulphonamide K finally yields4-tert.-butyl-N-[6-chloro-2-(4-cyanophenyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide.

EXAMPLE 70

In analogy to Example 3, from4-tert.-butyl-N-[2-(4-cyano-phenyl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide,sodium azide and ammonium chloride in DMF there is obtained4-tert.-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(4-1H-tetrazol-5-yl-phenyl)-pyrimidin-4-yl]-benzenesulphonamideas a white material.

EXAMPLE 71

In analogy to Example 1, from4-tert.-butyl-N-[6-chloro-2-(4-cyano-phenyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamidewith benzyloxyethanol sodium salt there is obtainedN-[6-(2-benzyloxy-ethoxy)-2-(4-cyano-phenyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert.-butyl-benzene-sulphonamideof melting point 158-159° C. from EtOAc.

EXAMPLE 72

In analogy to Example 3, fromN-[6-(2-benzyloxy-ethoxy)-2-(4-cyano-phenyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert.-butyl-benzenesulphonamide,sodium azide and ammonium chloride in DMF there is obtainedN-[6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(4-1H-tetrazol-5-yl-phenyl)-pyrimidin-4-yl]-4-tert.-butyl-benzenesulphonamideas a foam.

EXAMPLE 73

a) A solution of 2.1 g (3.4 mmol) of4-tert.-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamidein 40 ml of abs. THF is treated with 2 ml of1-(tert.-butyl-dimethylsilyl)-imidazole and heated to 50° while stirringfor one hour. The solution is evaporated under reduced pressure and theresidue is recrystallized from methylene chloride and isopropyl ether.There is thus obtained4-tert.-butyl-N-[6-[2-(tert.-butyl-dimethyl-silanyloxy)-ethoxy]-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamideof melting point 237-239° C. with decomposition.

b) A solution of 366.5 mg (0.5 mmol) of4-tert.-butyl-N-[6-[2-tert.-butyl-dimethyl-silanyloxy)-ethoxy]-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamidein 30 ml of abs. THF is treated at room temperature with 112.2 mg (1mmol) of potassium tert.-butylate and the suspension is heated at 40° C.while stirring for 30 min. 1 ml of ethyl bromide is added to the clearsolution and the solution is heated at 40° C. for 4 days. Thereafter,the solution is evaporated under reduced pressure, the residue is takenup in a 1:1 mixture of methylene chloride and ether and the organicsolution is washed three times with 0.5N NaHCO₃ and thereafter withwater. The organic extracts are dried with sodium sulphate andevaporated under reduced pressure. The residue is chromatographed onsilica gel with cyclohexane-EtOAc 1:1. Firstly there are isolated 100 mgof4-tert.-butyl-N-[6-[2-(tert.-butyl-dimethyl-silanyloxy)-ethoxy-2-[2-(2-ethyl-2H-tetrazol-5-yl)-pyridin-4-yl]-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamideand thereafter 100 mg of4-tert.-butyl-N-[6-[2-(tert.-butyl-dimethyl-silanyloxy)-2-[2-(1-ethyl-1H-tetrazol-5-yl)-pyridin-4-yl]-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide.

c) A solution of 90 mg of4-tert.-butyl-N-[6-[2-(tert.-butyl-dimethyl-silanyloxy)-ethoxy-2-[2-(2-ethyl-2H-tetrazol-5-yl)-pyridin-4-yl]-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzene-sulphonamidein 4 ml of CH₃ CN--H₂ O 1:1 is treated with 5 drops of trifluoroaceticacid and left at room temperature for 24 hours. Thereafter, acetonitrileis evaporated at 30° C. under reduced pressure and the aqueous phase istreated firstly with 1N NaOH, then with glacial acetic acid to pH 4 andextracted with ether. The organic extracts are washed with H₂ O, driedwith sodium sulphate and evaporated under reduced pressure. There isthus obtained4-tert.butyl-N-[2-[2-(2-ethyl-2H-tetrazol-5-yl)-pyridin-4-yl]-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]benzenesulphonamideas a yellowish foam. Analogously, from4-tert.-butyl-N-[6-[2-(tert.-butyl-dimethyl-silanyloxy)-2-[2-(1-ethyl-1H-tetrazol-5-yl)-pyridin-4-yl]-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamidethere is obtained4-tert.butyl-N-[2-[2-(1-ethyl-1H-tetrazol-5-yl)-pyridin-4-yl]-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]benzenesulphonamideas a yellowish foam.

EXAMPLE A

Tablets containing the following ingredients can be produced in aconventional manner:

    ______________________________________                                        Ingredients      Per tablet                                                   ______________________________________                                        Compound of formula I                                                                          10.0-100.0    mg                                               Lactose 125.0 mg                                                              Corn starch 75.0 mg                                                           Talc 4.0 mg                                                                   Magnesium stearate 1.0 mg                                                   ______________________________________                                    

EXAMPLE B

Capsules containing the following ingredients can be produced in aconventional manner:

    ______________________________________                                        Ingredients       Per capsule                                                 ______________________________________                                        Compound of formula I                                                                           25.0 mg                                                       Lactose 150.0 mg                                                              Corn starch 20.0 mg                                                           Talc  5.0 mg                                                                ______________________________________                                    

EXAMPLE C

Injection solutions can have the following composition:

    ______________________________________                                        a) Compound of formula I, e.g.                                                  4-tert.butyl-N-[6-(2-hydroxy-ethoxy)-5- 3.0 mg                                (2-methoxy-phenoxy)-2-(2-1H-tetrazol-                                         5-yl)-pyridin-4-yl]-pyrimidin-4-yl]-                                          benzenesulphonamide disodium salt                                             Gelatine 150.0 mg                                                             Water for injection solutions ad 1.0 ml                                       b) Compound of formula I, e.g.                                                5-methyl-pyridine-2-sulphonic acid 6- 5.0 mg                                  (2-hydroxy-ethoxy)-5-(2-methoxy-                                              phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-                                       4-yl)-pyrimidin-4-ylamide disodium salt                                       Gelatine 150.0 mg                                                             Water for injection solutions ad 1.0 ml                                       c) Compound of formula I, e.g.                                                5-isopropyl-pyridine-2-sulphonic acid 6- 5.0 mg                               (2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-                                     2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-                                          pyrimidin-4-ylamide disodium salt                                             Gelatine 150.0 mg                                                             Water for injection solutions ad 1.0 ml                                     ______________________________________                                    

EXAMPLE D

500 mg of compound of formula I are suspended in 3.5 ml of Myglyol 812and 0.08 g of benzyl alcohol. This suspension is filled into a containerhaving a dosage valve. 5.0 g of Freon 12 are filled into the containerunder pressure through the valve. The Freon is dissolved in theMyglyol-benzyl alcohol mixture by shaking. This spray container containsabout 100 single doses which can be applied individually.

We claim:
 1. A compound of the formula: ##STR5## wherein R¹ is phenyl;phenyl substituted with halogen, C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇-alkylenedioxy, carboxyl, or trifluoromethyl; or heterocyclyl selectedfrom the group consisting of mono- or bicyclic, 5- and 6-memberedheterocycles having oxygen, nitrogen or sulphur as the hetero atom;R² istetrazolyl, C₁₋₇ -alkyl-substituted tetrazolyl, cyano, carboxy, C₁₋₇-alkoxycarbonyl, hydroxymethyl, formyl, carbamoyl, thiocarbamoyl,amidino, or hydroxyamidino; R³ is --O--(CR^(a) R^(b))_(n) --OR⁹ ; R⁴ -R⁸are each independently hydrogen, C₁₋₇ -alkoxy, or halogen; R⁹ ishydrogen; benzyl; benzyl substituted on the phenyl ring by halogen, C₁₋₇-alkyl, C₁₋₇ -alkoxy, C₁₋₇ -alkylenedioxy, carboxyl, or trifluoromethyl;or --C(O)NHR¹⁰ ; R¹⁰ is C₁₋₇ -alkyl; phenyl; phenyl substituted withhalogen, C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇ -alkylenedioxy, carboxyl, ortrifluoromethyl; pyridyl; or pyridyl substituted by 1 or 2 C₁₋₇ -alkylgroups; R^(a) and R^(b) are each hydrogen or C₁₋₇ -alkyl; n is2, 3, or4; A and B are each CH; or one of A and B is nitrogen and the other isCH; or a pharmaceutically usable salt thereof.
 2. The compound of claim1, wherein R⁹ is hydrogen, benzyl, benzyl substituted on the phenyl ringby halogen, C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇ -alkylenedioxy, carboxyl, ortrifluoromethyl; or --C(O)NHR¹⁰.
 3. The compound of claim 1, wherein Aand B are CH.
 4. The compound of claim 1, wherein one of A and B isnitrogen and the other is CH.
 5. The compound of claim 4, wherein A isnitrogen and B is CH.
 6. The compound of claim 1, wherein R² istetrazolyl or C₁ -C₇ -alkyl-substituted tetrazolyl.
 7. The compound ofclaim 1, wherein R¹ is (i) phenyl that is substituted with one or twosubstituents selected from the group consisting of halogen, lower-alkyl,C₁ -C₇ -alkoxy, C₁ -C₇ -alkylenedioxy, carboxyl, and trifluoromethyl, or(ii) pyridyl that is mono-substituted with alkyl; and R³ is --O(CH₂)_(n)OH, --O(CH₂)_(n) O-benzyl, or --O(CH₂)_(n) OC(O)NHR¹⁰.
 8. The compoundaccording to claim 1, wherein R⁴ is C₁₋₇ -alkoxy and R⁵ -R⁸ arehydrogen.
 9. The compound according to claim 1, wherein R⁴ is halogen,R⁷ is C₁₋₇ -alkoxy, and R⁵, R⁶ and R⁸ are hydrogen.
 10. The compoundaccording to claim 6, wherein the compound of formula I is5-methyl-pyridine-2-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide.11. The compound according to claim 6, wherein the compound of formula Iis4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide.12. The compound according to claim 6, wherein the compound of formula Iis2-[6-(4-tert-butyl-phenylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl-oxy]-ethylpyridin-2-ylcarbamate.
 13. The compound according to claim 6, whereinthe compound of formula I isN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide.14. The compound according to claim 6, wherein the compound of formula IisN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-4-methyl-benzenesulphonamide.15. The compound according to claim 6, wherein the compound of formula IisN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-4-methoxy-benzenesulphonamide.16. The compound according to claim 6, wherein the compound of formula IisN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-4-methylsulphanyl-benzenesulphonamide.17. The compound according to claim 6, wherein the compound of formula Iis 1,3-benzodioxol-5-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide.18. The compound according to claim 6, wherein the compound of formula IisN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-3,4-dimethoxy-benzenesulphonamide.19. The compound according to claim 6, wherein the compound of formula IisN-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-2,5-dimethoxy-benzolsulphonamide.20. The compound according to claim 6, wherein the compound of formula Iis pyridine-3-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylmide.21. The compound according to claim 6, wherein the compound of formula Iis4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide.22. The compound according to claim 6, wherein the compound of formula Iis 1,3-benzodioxol-5-sulphonic acid[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-amide.23. The compound according to claim 6, wherein the compound of formula Iis 5-isopropyl-pyridin-2-sulphonic acid[5-(2-chloro-5-methoxy-phenoxy)-6-(2-hydroxy-ethoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-amide.24. The compound according to claim 6, wherein the compound of formula Iis4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[6-(1H-tetrazol-5-yl)-pyridin-2-yl]-pyrimidin-4-yl]-benzenesulphonamide.25. The compound according to claim 6, wherein the compound of formula Iis2-[5-(2-methoxy-phenoxy)-6-phenylsulphonylamino-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxyl-ethylpyridin-2-ylcarbamate.
 26. The compound according to claim 6, whereinthe compound of formula I is2-[5-(2-methoxy-phenoxy)-6-(4-methyl-phenylsulphonylamino)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.
 27. The compound according to claim 6, whereinthe compound of formula I is2-[5-(2-methoxy-phenoxy)-6-(4-methyl-phenylsulphonylamino)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl1,3-benzodioxol-5-ylcarbamate.
 28. The compound according to claim 6,wherein the compound of formula I is2-[5-(2-methoxy-phenoxy)-6-(4-methylsulphanylphenyl-sulphonylamino)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.
 29. The compound according to claim 6, whereinthe compound of formula I is2-[6-(1,3-benzodioxol-5-ylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.
 30. The compound according to claim 6, whereinthe compound of formula I is2-[6-(1,3-benzodioxol-5-ylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl1,3-benzodioxol-5-ylcarbamate.
 31. The compound according to claim 6,wherein the compound of formula I is2-[6-(3,4-dimethoxy-phenylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.
 32. The compound according to claim 6, whereinthe compound of formula I is2-[5-(2-methoxy-phenoxy)-6-(2,5-dimethoxy-phenyl-sulphonylamino)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-2-yloxy]-ethylpyridin-2-ylcarbamate.
 33. The compound according to claim 6, whereinthe compound of formula I is2-[5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-6-pyridin-3-ylsulphonylamino-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.
 34. The compound according to claim 6, whereinthe compound of formula I is2-[5-(2-methoxy-phenoxy)-6-pyridin-3-ylsulphonylamino-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl1,3-benzodioxol-5-ylcarbamate.
 35. The compound according to claim 6,wherein the compound of formula I is2-[5-(2-methoxy-phenoxy)-6-(5-methyl-pyridin-2-yl-sulphonylamino)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.
 36. The compound according to claim 6, whereinthe compound of formula I is2-[6-(5-isopropyl-pyridin-2-ylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.
 37. The compound according to claim 6, whereinthe compound of formula I is2-[6-(5-isopropyl-pyridin-2-ylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl1,3-benzodioxol-5-ylcarbamate.
 38. The compound according to claim 6,wherein the compound of formula I is2-[6-(4-tert-butyl-phenylsulphonylamino)-5-(2-chloro-5-methoxy-phenoxy)-2-(2-1H-tertrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.
 39. The compound according to claim 6, whereinthe compound of formula I is2-[6-(1,3-benzodioxol-5-ylsulphonylamino)-5-(2-chloro-5-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.
 40. The compound according to claim 6, whereinthe compound of formula I is2-[6-(4-tert-butyl-phenylsulphonylamino)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-2-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.
 41. The compound according to claim 6, whereinthe compound of formula I isN-[6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphonamide.42. The compound according to claim 6, wherein the compound of formula Iis4-tert-butyl-N-[2-[2-(1-ethyl-1H-tetrazol-5-yl)-pyridin-4-yl]-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]benzenesulphonamide.43. The compound according to claim 1, wherein the compound of formula Iis4-tert-butyl-N-[2-(3-cyano-phenyl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide.44. The compound according to claim 1, wherein the compound of formula Iis4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(3-1H-tetrazol-5-yl-phenyl)-pyrimidin-4-yl]-benzenesulphonamide.45. The compound according to claim 1, wherein the compound of formula Iis2-[6-(4-tert-butyl-phenylsulphonyl)-5-(2-methoxy-phenoxy)-2-(3-1H-tetrazol-5-yl-phenyl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.
 46. The compound according to claim 1, whereinthe compound of formula I isN-[6-(2-benzyloxy-ethoxy)-2-(3-cyano-phenyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphonamide.47. The compound according to claim 1, wherein the compound of formula IisN-[6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(3-1H-tetrazol-5-yl-phenyl)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphonamide.
 48. The compound according to claim 1,wherein the compound of formula I is4-tert-butyl-N-[2-(4-cyano-phenyl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide.49. The compound according to claim 1, wherein the compound of formula Iis4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(4-1H-tetrazol-5-yl-phenyl)-pyrimidin-4-yl]-benzenesulphonamide.50. The compound according to claim 1, wherein the compound of formula IisN-[6-(2-benzyloxy-ethoxy)-2-(4-cyano-phenyl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphonamide.51. The compound according to claim 1, wherein the compound of formula IisN-[6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(4-1H-tetrazol-5-yl-phenyl)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphonamide.52. The compound according to claim 4, wherein the compound of formula Iis4-tert-butyl-N-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide.53. The compound according to claim 4, wherein the compound of formula IisN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide.54. The compound according to claim 4, wherein the compound of formula IisN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-methylbenzenesulphonamide.
 55. The compound according to claim 4, wherein thecompound of formula I isN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-methoxy-benzenesulphonamide.56. The compound according to claim 4, wherein the compound of formula IisN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-methylsulphanyl-benzenesulphonamide.57. The compound according to claim 4, wherein the compound of formula Iis 1,3-benzodioxol-5-sulphonic acid2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamide.58. The compound according to claim 4, wherein the compound of formula IisN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-3,4-dimethoxy-benzene-sulphonamide.59. The compound according to claim 4, wherein the compound of formula IisN-[2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-2,5-dimethoxy-benzene-sulphonamide.60. The compound according to claim 4, wherein the compound of formula Iis pyridine-3-sulphonic acid2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamide.61. The compound according to claim 4, wherein the compound of formula Iis 5-methyl-pyridine-2-sulphonic acid2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamide.62. The compound according to claim 4, wherein the compound of formula Iis 5-isopropyl-pyridine-2-sulphonic acid2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-ylamide.63. The compound according to claim 4, wherein the compound of formula Iis4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-yl]-benzenesulphonamide.64. The compound according to claim 4, wherein the compound of formula Iis 1,3-benzodioxol-5-sulphonic acid5-(2-chloro-5-methoxy-phenoxy)-2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-ylamide.65. The compound according to claim 4, wherein the compound of formula Iis 5-isopropyl-pyridine-2-sulphonic acid5-(2-chloro-5-methoxy-phenoxy)-2-(2-cyano-pyridin-4-yl)-6-(2-hydroxy-ethoxy)-pyrimidin-4-ylamide.66. The compound according to claim 4, wherein the compound of formula Iis4-tert-butyl-N-[2-(6-cyano-pyridin-2-yl)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide.67. The compound according to claim 4, wherein the compound of formula IisN-[6-(2-benzyloxy-ethoxy)-2-(2-cyano-pyridin-4-yl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-4-tert-butyl-benzenesulphon-amide.68. The compound according to claim 4, wherein the compound of formula Iis 5-isopropyl-pyridine-2-sulphonicacid-N-[6-(2-benzyloxy-ethoxy)-2-(2-cyanopyridin-4-yl)-5-(2-methoxyphenoxy)-pyrimidin-4-yl]-amide.69. The compound according to claim 4, wherein the compound of formula Iis4-tert-butyl-N-[2-[2-(amino-imino-methyl)-pyridin-4-yl]-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide.70. The compound according to claim 3, wherein the compound of formula Iis ethyl4-[4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboxylate.71. The compound according to claim 3, wherein the compound of formula Iis4-[4-(4-tert-butyl-phenylsulphonylamino)-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboxylicacid.
 72. The compound according to claim 6, wherein the compound offormula I is2-[5-(2-methoxy-phenoxy)-6-(4-methyl-phenylsulphonyl-amino)-2-(2-1H-tetrazol-5-yl-pyridin-2-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.
 73. The compound according to claim 6, whereinthe compound of formula I is2-[5-(2-methoxy-phenoxy)-6-(4-methoxy-phenylsulphonyl-amino)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-yloxy]-ethyl1,3-benzodioxol-5-ylcarbamate.
 74. The compound according to claim 6,wherein the compound of formula I is2-[5-(2-chloro-5-methoxy-phenoxy)-6-(5-isopropyl-pyridin-2-ylsulphonylamino)]-2-(2-1H-tertrazol-5-yl-pyridin-2-yl)-pyrimidin-4-yloxy]-ethylpyridin-2-ylcarbamate.
 75. The compound according to claim 6, whereinthe compound of formula I is 5-methyl-pyridine-2-sulphonic acid[6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tertrazol-5-yl-pyridin-4-yl)]-amide.
 76. The compound according to claim 6, wherein the compound offormula I is 5-isopropyl-pyridine-2-sulphonic acid[6-(2-benzyloxy-ethoxy)-5-(2-methoxy-phenoxy)-2-[2-(1H-tetrazol-5-yl)-pyridin-4-yl]-pyrimidin-4-yl]-amide.77. The compound according to claim 6, wherein the compound of formula Iis4-tert-butyl-N-[2-[2-(hydroxyamino-imino-methyl)-pyridin-4-yl]-6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-benzenesulphonamide.78. The compound according to claim 6, wherein the compound of formula Iis 5-isopropyl-pyridine-2-sulphonic acid6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide.79. A step in a process for making a compound of the formula: ##STR6##wherein R¹ is phenyl; phenyl substituted with halogen, C₁₋₇ -alkyl, C₁₋₇-alkoxy, C₁₋₇ -alkylenedioxy, carboxyl, or trifluoromethyl; orheterocyclyl selected from the group consisting of mono- or bicyclic, 5-and 6-membered heterocycles having oxygen, nitrogen or sulphur as thehetero atom;R² is tetrazolyl, C₁₋₇ -alkyl-substituted tetrazolyl, cyano,carboxy, C₁₋₇ -alkoxycarbonyl, hydroxymethyl, formyl, carbamoyl,thiocarbamoyl, amidino, or hydroxyamidino; R³ is --O--(CR^(a) R^(b))_(n)--OR⁹ ; R⁴ -R⁸ are each independently hydrogen, C₁₋₇ -alkoxy, orhalogen; R⁹ is hydrogen; benzyl; benzyl substituted on the phenyl ringby halogen, C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇ -alkylenedioxy, carboxyl, ortrifluoromethyl; or --C(O)NHR¹⁰ ; R¹⁰ is C₁₋₇ -alkyl; phenyl; phenylsubstituted with halogen, C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇-alkylenedioxy, carboxyl, or trifluoromethyl; pyridyl; or pyridylsubstituted by 1 or 2 C₁₋₇ -alkyl groups; R^(a) and R^(b) are eachhydrogen or C₁₋₇ -alkyl; n is 2, 3, or 4; A and B are each CH; or one ofA and B is nitrogen and the other is CH; which comprises: reacting acompound of the formula: ##STR7## wherein R¹² is 3-cyanophenyl,4-cyanophenyl, 2-pyridyl-N-oxide, or 4-pyridyl-N-oxide;Hal is halogen;and R¹, R⁴, R⁵, R⁶, R⁷, and R⁸ are as above; with a compound of theformula MO--(CR^(a) R^(b))_(n) --OR⁹¹, wherein M is an alkali metal; R⁹¹is hydrogen; benzyl; benzyl substituted on the phenyl ring by halogen,C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇ -alkylenedioxy, carboxyl, ortrifluoromethyl; and R^(a), R^(b), and n are as above.
 80. A step in aprocess for making a compound of the formula: ##STR8## wherein R¹ isphenyl; phenyl substituted with halogen, C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇-alkylenedioxy, carboxyl, or trifluoromethyl; or heterocyclyl selectedfrom the group consisting of mono- or bicyclic, 5- and 6-memberedheterocycles having oxygen, nitrogen or sulphur as the hetero atom;R² istetrazolyl, C₁₋₇ -alkyl-substituted tetrazolyl, cyano, carboxy, C₁₋₇-alkoxycarbonyl, hydroxymethyl, formyl, carbamoyl, thiocarbamoyl,amidino, or hydroxyamidino; R³ is --O--(CR^(a) R^(b))_(n) --OR⁹ ; R⁴ -R⁸are each independently hydrogen, C₁₋₇ -alkoxy, or halogen; R⁹ ishydrogen; benzyl; benzyl substituted on the phenyl ring by halogen, C₁₋₇-alkyl, C₁₋₇ -alkoxy, C₁₋₇ -alkylenedioxy, carboxyl, or trifuoromethyl;or --C(O)NHR¹⁰ ; R¹⁰ is C₁₋₇ -alkyl; phenyl; phenyl substituted withhalogen, C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇ -alkylenedioxy, carboxyl, ortrifluoromethyl; pyridyl; or pyridyl substituted by 1 or 2 C₁₋₇ -alkylgroups; R^(a) and R^(b) are each hydrogen or C₁₋₇ -alkyl; n is 2, 3, or4; A and B are each CH; or one of A and B is nitrogen and the other isCH; or R² is hydrogen and one of A and B is N-oxide and the other is CH;which comprises: reacting a compound of the formula: ##STR9## whereinR¹¹ is 2-pyridyl-N-oxide, or 4-pyridyl-N-oxide; andR¹, R³, R⁴, R⁵, R⁶,R⁷, and R⁸ are as above; with a trialkylsilyl cyanide and atrialkylamine.
 81. A pharmaceutical composition which comprises:(a) from3 mg to 100 mg of a compound of the formula: ##STR10## wherein R¹ isphenyl; phenyl substituted with halogen, C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇-alkylenedioxy, carboxyl, or trifluoromethyl; or heterocyclyl selectedfrom the group consisting of mono- or bicyclic, 5- and 6-memberedheterocycles having oxygen, nitrogen or sulphur as the hetero atom;R² istetrazolyl, C₁₋₇ -alkyl-substituted tetrazolyl, cyano, carboxy, C₁₋₇-alkoxycarbonyl, hydroxymethyl, formyl, carbamoyl, thiocarbamoyl,amidino, or hydroxyamidino; R³ is --O--(CR^(a) R^(b))_(n) --OR⁹ ; R⁴ -R⁸are each independently hydrogen, C₁₋₇ -alkoxy, or halogen; R⁹ ishydrogen; benzyl; benzyl substituted on the phenyl ring by halogen, C₁₋₇-alkyl, C₁₋₇ -alkoxy, C₁₋₇ -alkylenedioxy, carboxyl, or trifluoromethyl;or --C(O)NHR¹⁰ ; R¹⁰ is C₁₋₇ -alkyl; phenyl; phenyl substituted withhalogen, C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇ -alkylenedioxy, carboxyl, ortrifluoromethyl; pyridyl; or pyridyl substituted by 1 or 2 C₁₋₇ -alkylgroups; R^(a) and R^(b) are each hydrogen or C₁₋₇ -alkyl; n is 2, 3, or4; A and B are each CH; or one of A and B is nitrogen and the other isCH; or a pharmaceutically usable salt thereof; and (b) a therapeuticallyinert carrier.
 82. The pharmaceutical composition of claim 81, whereinthe composition comprises 3 mg of a compound of formula I.
 83. Thepharmaceutical composition of claim 81, wherein the compositioncomprises 5 mg of the compound of formula I.
 84. The pharmaceuticalcomposition of claim 81, wherein the composition comprises from 10 mg to100 mg of the compound of formula I.
 85. The pharmaceutical compositionof claim 84, wherein the composition comprises from 25 mg of thecompound of formula I.
 86. A method of treating circulatory disorders,which comprises administering to a host in need of such treatment aneffective amount of the compound of the formula: ##STR11## wherein R¹ isphenyl; phenyl substituted with halogen, C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇-alkylenedioxy, carboxyl, or trifluoromethyl; or heterocyclyl selectedfrom the group consisting of mono- or bicyclic, 5- and 6-memberedheterocycles having oxygen, nitrogen or sulphur as the hetero atom;R² istetrazolyl, C₁₋₇ -alkyl-substituted tetrazolyl, cyano, carboxy, C₁₋₇-alkoxycarbonyl, hydroxymethyl, formyl, carbamoyl, thiocarbamoyl,amidino, or hydroxyamidino; R³ is --O--(CR^(a) R^(b))_(n) --OR⁹ ; R⁴ -R⁸are each independently hydrogen, C₁₋₇ -alkoxy, or halogen; R⁹ ishydrogen; benzyl; benzyl substituted on the phenyl ring by halogen, C₁₋₇alkyl, C₁₋₇ -alkoxy, C₁₋₇ -alkylenedioxy, carboxyl, or trifluoromethyl;or --C(O)NHR¹⁰ ; R¹⁰ is C₁₋₇ -alkyl; phenyl; phenyl substituted withhalogen, C₁₋₇ -alkyl, C₁₋₇ -alkoxy, C₁₋₇ -alkylenedioxy, carboxyl, ortrifluoromethyl; pyridyl; or pyridyl substituted by 1 or 2 C₁₋₇ -alkylgroups; R^(a) and R^(b) are each hydrogen or C₁₋₇ -alkyl; n is 2, 3, or4; A and B are each CH; or one of A and B is nitrogen and the other isCH; or a pharmaceutically usable salt thereof.